No single advance at the frontier between biology and chemistry will transform research in the life sciences more than the synthesis of an artificial life form (a ?xenobiotic?). This xenobiotic will reproduces much of what we value in natural life (including its ability to grow, evolve and adapt), but with a different core molecular biology. This would move beyond the visions of ?synthetic biology? and ?biomimetic chemistry?, the second recognized just this week with a Nobel Prize in chemistry, to deliver an artificial biology, a new field that will transform both biomedical science and technology for decades to come. This goal transcends the current orientation of the NIH towards ?descriptive biology?, a research paradigm that is already well represented in the Director?s portfolio. Indeed, we begin by assuming that those now supported by the Director in these now-classical descriptive strategies will eventually complete this research programme, producing robust pictures of biomolecular structure from the atomic scale to the macroscopic scale. The work proposed here will lay the grounds for the life sciences that will follow next. A paradox is built into any application to do transformative research. If it is truly transformative, one cannot anticipate the details of its impact. This is problematic for peer review. To manage this paradox, we list a half- dozen technological capabilities that our artificial life form should deliver based on what in vitro preliminary work has already delivered. These include transforming the way we generate clinically used receptors, ligands, and catalysts, lowering the cost of diagnostic kit production, and creating new classes of engineered proteins. An analogous paradox arises respect to the science. Many now argue that the touchstone for ?understanding? must be the ability to design and synthesize. However, we recognize that theory (now, and far into the future) is inadequate to design without support from Darwinism. Our global strategy therefore combines design and Darwinism. This strategy for discovery and paradigm change cannot be matched by hypothesis based research. Again, discovery and paradigm change cannot be predicted, creating another peer review issue. We manage this by examples from in vitro studies, which have transformed our understanding of nucleic acids. Consequently, this proposal contains an unexpectedly large number of preliminary results. This places it at risk of being excluded from a transformative research program under a hope can its transformation can funded as a standard NIH project. This hope has been fully shown to be quixotic; the experiment has been repeatedly tried and failed, in part because of the high risk still associated with efforts to achieve the first needed breakthrough. To manage this risk, the program is structured to give many routes to success. Balancing this is the unarguable fact that if any one of the routes to success is traversed, the result (an artificial Darwinian life form) will be as memorable as any of the many accomplishments in the history of biological-chemical science. Last, we provide a detailed discussion of biosafety with respect to artificial life.